Dataset Information

Differences of adrenal-derived androgens in 5α-reductase deficiency versus androgen insensitivity syndrome.

ABSTRACT: Steroid 5α-reductase type 2 deficiency (5α-RD2) and androgen insensitivity syndrome (AIS) are difficult to distinguish clinically and biochemically, and adrenal-derived androgens have not been investigated in these conditions using modern methods. The objective of the study was to compare Chinese patients with 5α-RD2, AIS, and healthy men. Sixteen patients with 5α-RD2, 10 patients with AIS, and 39 healthy men were included. Serum androgen profiles were compared in these subjects using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Based on clinical features and laboratory tests, 5α-RD2 and AIS were diagnosed and confirmed by genotyping. Dihydrotestosterone (DHT) and testosterone (T) were both significantly lower in patients with 5α-RD2 than AIS (p < 0.0001). The T/DHT ratio was higher in 5α-RD2 (4.5-88.6) than AIS (13.4-26.7) or healthy men (7.6-40.5). Using LC-MS/MS, a cutoff T/DHT value of 27.3 correctly diagnosed 5α-RD2 versus AIS with sensitivity 93.8% and specificity 100%. Among the adrenal-derived 11-oxygenated androgens, 11β-hydroxyandrostenedione (11OHA4) and 11-ketoandrostenedione (11KA4) were also lower in patients with 5α-RD2 than those of patients with AIS. In contrast, 11β-hydroxytestosterone (11OHT) was higher in 5α-RD2 than AIS. Furthermore, a 11OHT/11OHA4 cutoff value of 0.048 could also distinguish 5α-RD2 from AIS. Thus, both elevated T/DHT values above 27.3 and the unexpected 11-oxygenated androgen profile, with a 11OHT/11OHA4 ratio greater than 0.048, distinguished 5α-RD2 from AIS. These data suggest that the metabolism of both gonadal and adrenal-derived androgens is altered in 5α-RD2.

SUBMITTER: Han B

PROVIDER: S-EPMC8932821 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Differences of adrenal-derived androgens in 5α-reductase deficiency versus androgen insensitivity syndrome.

Han Bing B Zhu Hui H Yao Haijun H Ren Jianwei J O'Day Patrick P Wang Hao H Zhu Wenjiao W Cheng Tong T Auchus Richard J RJ Qiao Jie J

Clinical and translational science 20211111 3

Steroid 5α-reductase type 2 deficiency (5α-RD2) and androgen insensitivity syndrome (AIS) are difficult to distinguish clinically and biochemically, and adrenal-derived androgens have not been investigated in these conditions using modern methods. The objective of the study was to compare Chinese patients with 5α-RD2, AIS, and healthy men. Sixteen patients with 5α-RD2, 10 patients with AIS, and 39 healthy men were included. Serum androgen profiles were compared in these subjects using liquid chr ...[more]

PMID: 34755921

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Project description:BackgroundPreviously, we studied the effect of finasteride- or dutasteride-containing diets in male C57BL/6 TRAMP x FVB mice. Pre (6 weeks of age) and post (12 weeks of age) groups received finasteride or dutasteride to determine the efficacy of these pharmaceuticals on prostate cancer (PCa) development in male C57BL/6 TRAMP x FVB mice. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment, and dutasteride treatments were more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia (PIN) progression and PCa development. Finasteride and Pre-Dutasteride treatments significantly decreased high-grade PIN incidence, but increased poorly differentiated PCa incidence. In this study, molecular changes in prostates of these mice were characterized in an effort to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and determine why Post-Dutasteride treatment was more effective.Method/principal findingsKi-67 (proliferation marker) and androgen receptor (AR) protein, apoptotic DNA fragmentation (TUNEL assay), 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) mRNA were quantified in male TRAMP mice prostate tissues with genitourinary weight < 1 and > 1 gram. Overall, proliferation and AR were decreased and apoptosis was increased in most tumors versus prostate epithelium and hyperplasia. Proliferation and AR were increased notably in hyperplasia versus prostate epithelium and tumor. There were no clear trends or differences in 5α-reductase 1 and 5α-reductase 2 levels between large and small tumors. The discordant response in Pre-Finasteride and Pre-Dutasteride groups may be due to upregulated 5αR1 levels in large versus small tumors. It is not clear what the mechanism is for the different response in the Post-Finasteride group. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment in decreasing 5αR1 in large tumors. Therefore, this may be why this treatment was more effective in decreasing PIN progression and PCa development.ConclusionThe effect of finasteride and dutasteride on these biomarkers did not clearly elucidate their mechanism of action, but tumor 5αR1 levels were significantly positively correlated with adjusted prostate severe lesion score.

Project description:Prostate cancers (PCs), initially responsive to anti-androgen therapies, often advance to a hormone-refractory 'castrate-resistant' PC (CRPC) stage. However, the androgen receptor (AR) pathway remains active and key for cell growth and gene expression within tumours, even in the apparent absence of hormone. Proposed mechanisms to explain progression, including AR amplification/mutation, are insufficient to completely explain CRPC and possible roles of AR cofactors such as prohibitin (PHB) are poorly understood. We investigated whether PHB loss could sensitise PC cells and tumours to adrenal gland-derived androgens, which persist even after androgen ablation, hence contribute to development of CRPC. Using a pair of PC cell lines, inducibly expressing ectopic cDNA or RNAi for PHB, responses to different androgens and hormone concentrations were studied both in vitro and in vivo. PHB was found at the promoters of several genes, both AR and non-AR-regulated, and knockdown increased histone acetylation at these promoters. Further, PHB knockdown increased the rate of AR ligand-induced chromatin binding, and binding rate and occupancy of AR upon the PSA promoter. This resulted in increased cell growth and AR activity in response to all androgens, including promoting a response to the weaker adrenal androgens previously absent at physiological concentrations. In vivo this had functional consequences such that PHB knockdown resulted in androstenedione being sufficient to promote tumour growth, under conditions mimicking those in patients undergoing androgen ablation therapy. We conclude that reduction in PHB levels is sufficient to lower the threshold of AR activity in vitro and in vivo; this may be via a general increase in histone acetylation that could potentially affect signalling by other transcription factors. PHB loss may provide a mechanism for progression to CRPC by sensitising PC cells to 'castrate' conditions-that is, low levels of testicular androgens in the continued presence of weak adrenal and dietary androgens.

Dataset Information

Differences of adrenal-derived androgens in 5α-reductase deficiency versus androgen insensitivity syndrome.

Publications

Differences of adrenal-derived androgens in 5α-reductase deficiency versus androgen insensitivity syndrome.

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